Tricyclic imidazole derivatives

ABSTRACT

New tricyclic fused imidazole derivatives of the general formula (I), ##SPC1## 
     wherein 
     R 1  stands for hydrogen or hydroxy, 
     n is equal to zero or one, 
     m is equal to zero, one or two, 
     A stands for a group of the general formula (II), ##EQU1##   wherein R 2  represents hydrogen or hydroxy, 
     R 3  represents hydrogen or amino, or 
     Q and Z each stand for nitrogen or a =C-- group, or 
     A stands for a group of the general formula (III), ##EQU2##  wherein R 4  and R 5  each represent hydrogen, methyl, chlorine or nitro, 
     Were prepared by reacting a compound of the general formula (IV) ##SPC2## 
     wherein A and n each have the same meanings as defined above, with a compound of the general formula (V), ##EQU3## wherein X stands for halogen, R 6  stands for hydrogen and R 7  stands for a group of the general formula (VI), 
     
         --(CH.sub.2).sub.m --X                                     (VI) 
    
     in which m and X each have the same meanings as defined above, or R 6  and R 7  together stand for oxygen. The reaction is carried out optionally in the presence of a base. The compounds of the general formula (I) can be converted into their acid addition salts. 
     The compounds of the general formula (I) as well as their acid addition salts exert antipyretic and antiphlogistic activities, inhibit the reproduction of viruses, and exert a protecting effect against albumine shock.

This invention relates to new tricyclic fused imidazole derivatives andacid addition salts thereof, and a process for the preparation of thesecompounds.

The compounds according to the invention correspond to the generalformula (I) ##SPC3##

wherein

R₁ stands for hydrogen or hydroxy,

n is equal to zero or one,

m is equal to zero, one or two,

A stands for a group of the general formula (II), ##EQU4## wherein R₂represents hydrogen or hydroxy,

R₃ represents hydrogen or amino, and

Q and Z each stand for nitrogen or a =CH-- group, or

A stands for a group of the general formula (III), ##EQU5## wherein R₄and R₅ each represent hydrogen, methyl, chlorine or nitro.

We have found that the compounds of the general formula (I) possessvaluable pharmacological properties. More particularly, these compoundsexert antipyretic and antiphlogistic activities, inhibit thereproduction of viruses, and exert a protecting effect against albumineshock.

As regards the antipyretic and antiphlogistic activities, compounds ofthe general formula (I), wherein A stands for a group of the generalformula (II) and R₂ and R₃ each represent hydrogen or R₂ stands forhydroxy and R₃ stands for amino, or A represents a group of the generalformula (III), wherein R₄ and R₅ are the same and stand for hydrogen ofmethyl, are the most advantageous ones. Of these compounds3,4-dihydro-2H-(1,3)-thiazino[3,2-a]pyrido[3,2-d]imidazole is the mostactive one.

A protecting effect against albumine shock is exerted primarily by thecompounds that contain a group of the general formula (III) as Asubstituent and hydroxy as R₁ substituent. Of these compounds3,4-dihydro-3-hydroxy-2H-(1,3)-thiazino[3,2-a]benzimidazole proved to bethe most active one.

As regards the inhibiting effect exerted on the reproduction of viruses,compounds of the general formula (I) wherein R₁ stands for hydroxyproved to be the most advantageous. In this group3,4-dihydro-3-hydroxy-7,8-dimethyl-2H-(1,3)-thiazino[3,2-a]benzimidazoleshows the most potent effect.

The antipyretic effect of the compounds was examined according to themethod of Winder (C. V. Winder et al.: Pharmac. exp. Ther. 138, 405(1963)). A 15 % yeast suspension was administered in a dosage of 1ml./100 g. body weight to male rats each weighing 210 ± 10 g. No foodwas given to the animals, they could consume water, however, ad libitum.16 Hours after the administration of yeast, the body temperature of theanimals was taken, and the compound to be tested was administered intothe animals orally through a tube. Thereafter the change in rectaltemperature of the animals was recorded for 5 hours, using an "Elab"type electrothermometer. During this period no water was given to theanimals. The results of the experiments carried out with3,4-dihydro-2H-(1,3)-thiazino[3,2-a]pyrido[3,2-d]imidazole aresummarized in Table 1. As the reference substance, phenacetine, a widelyapplied antipyretic was used.

                  Table 1                                                         ______________________________________                                        Substance   Dosage  Temperature change observed                                         mg./kg.                                                                             1       2       3    4    5                                                 hours after treatment, °C                                ______________________________________                                        3,4-dihydro-2H-                                                                           60      -1.2    -1.1  -1.0 -0.5 -0.6                              (1,3)-thiazino-                                                               [3,2-a]pyrido-                                                                            120     -1.8    -1.4  -1.8 -1.8 -1.1                              [3,2-d]imidazole                                                              Phenacetine 60      -1.3    -1.2  -1.5 -0.7 -1.0                                          120     -1.7    -2.1  -2.4 -1.6 -1.4                              ______________________________________                                    

The protecting effect against the anaphylaxic shock caused by albuminewas examined by Herxheimer's method (H. Herxheimer and E. Szersemann:Arch. int. Pharmacodyn. 125, 265 (1960)). Guinea pigs, each weighing 300to 400 g., were senzibilized by the intraperitoneal administration of a5 % eggalbumine solution. This treatment was repeated on the next day.Two weeks after the senzibilization, a 5% albumine solution wasinhalated by the animals in the form of an aerosol, and the time elapseduntil the development of shock was measured. The compound to be testedwas administered intraperitoneally in a dosage of 20 mg./kg. 30 minutesbefore the aerosol treatment. The test was carried out on groups eachconsisting of 6 animals. The animals showing no dyspnoe for 10 minuteswere considered as being protected. In this test3,4-dihydro-3-hydroxy-2H-(1,3)-thiazino[3,2-a]benzimidazole, in a dosageof 20 mg./kg., exerted a protective effect of 80%. The ED₅₀ value oftheophylline was 17 mg./kg. in the same test. On the basis of theseresults 3,4-dihydro-3-hydroxy-2H-(1,3)-thiazino[3,2-a]benzimidazole canbe regarded as an active therapeutic for the treatment of bronchialasthma.

The inhibiting effect exerted on virus reproduction was examined by theplaque method (S. Pacsa, O. Hankovszky, K. Hideg: Acta microbiol. Acad.Sci Hung. 12, 215 /1965/; S. Pacsa, O. Hankovszky, K. Hideg: Nature 208,409 /1965/). The tests were carried out on HEp-2 cell culturespropagated in a McCoy culture liquid containing 10% of inactivatedbovine serum. Monolayers of the culture were formed by introducing 5×10⁵or 10⁶ HEp-2 cells per dish into Petri dishes of 3 cm. or 5 cm.diameter, respectively, and incubating the system for 2 to 3 days at37°C. Thereafter the culture liquid was removed and the monolayers wereinoculated with 20 to 150 PFU (plaque forming units) of a polio 1 virusof Mahoney strain. After an absorption period of one hour at roomtemperature the cell cultures were covered with F-11 culture liquidcontaining agar and 0.5 % of bovine serum. 4 to 8 Petri dishes were usedfor the examination of each compound, adding the compounds in differentconcentrations to the individual dishes. The results were evaluated onthe third and fourth days of incubation. In this test the inhibitingeffect of3,4-dihydro-3-hydroxy-7,8-dimethyl-2H-(1,3)-thiazino[3,2-a]benzimidazolevaried between 50 to 95%, depending on the concentration.

The compounds of the general formula (I), wherein R₁, n, m, and A eachhave the same meanings as defined above, and the acid addition saltsthereof can be prepared according to the invention by reacting acompound of the general formula (IV) ##SPC4##

wherein A and n each have the same meanings as defined above, with acompound of the general formula (V), ##EQU6## wherein X stands forhalogen, R₆ stands for hydrogen and R₇ stands for a group of the generalformula (IV),

    --(CH.sub.2).sub.m -- X                                    (VI)

in which m and X each have the same meanings as defined above, or R₆ andR₇ together stand for oxygen, optionally in the presence of a base,preferably an alkali or alkaline earth metal hydroxide, and if desired,converting the obtained free bases into their acid addition salts, oralternately, converting the obtained salts into the free bases, and, ifdesired, separating the isomeric mixtures formed optionally into thepure isomers.

The compounds of the general formula (IV) may also exist in theirtautomeric forms, obtained by the migration of the hydrogen atom to theother nitrogen atom of the imidazole ring and the simultaneousrearrangement of the double bond. Such a tautomeric rearrangement occurswhen e.g. the hydrogen attached to the sulfur atom of the side chainmigrates to the nitrogen of the ring, and the double bond is shiftedsimultaneously between the sulfur atom and the adjacent carbon atom. Thethus formed thione compound is rearranged thereafter into the morestable thiol form, but in this rearrangement, either of the hydrogensattached to the ring nitrogens may migrate to othe sulfur atom. As aconsequence of these rearrangement reactions, the compound of thegeneral formula (IV) may exist in the form of two isomeric thiols.

If group A is symmetric, that is, the R₂, R₃ and Q, Z pairs in formula(II), or the R₄, R₅ pair in group (III) have the same meaning, thetautomeric thiol forms are the same in structure, i.e., the tautomery isonly apparent. Otherwise, i.e., when group A is asymmetric, thecompounds of the general formula (IV) exist in the form of two isomericthiols, in a concentration ratio depending on the tautomeric equilibriumconstant.

If the starting compounds of the general formula (IV) contain anasymmetric A substituent, the end-products of the general formula (I)obtained therefrom may also be mixtures of two isomers with the sameempirical formula.

Groups (II) and (III), represented by substituent A, may be attached tothe imidazole ring in compounds (I) and (IV) in two ways, and these twopossibilities represent the structures of the isomers existing as aconsequence of the above tautomeric rearrangement.

For the sake of clarity, each of the compounds (IV) and (I) that conatinan asymmetric A substituent is referred to in the specification and theclaims as a single compound, under the name of the isomeric form that ismore probable on the basis of the inductive effects of the substituents.

The acid binding agent and the reactant of the general formula (V) canbe added to the reaction mixture in any desired sequence. Preferably,the base acting as acid binding agent is added first, and then thereactant of the general formula (V) is added.

The organic or mineral base can be administered in solid state or in theform of a solution or suspension formed with water or an aqueous organicsolvent.

According to an advantageous method of the invention the separation ofthe halide salt by-product in the form of an insoluble precipitate fromthe end-product is promoted by an appropriate ratio of water and theorganic solvent.

The reaction of the compound having the general formula (IV) with acompound of the general formula (V) in the presence of an acid bindingagent is generally carried out at elevated temperatures, preferably atthe boiling point of the reaction mixture. The reaction is completedwhen the inorganic halide ceases to separate.

An acid binding agent, preferably an alkali or alkaline earth metalhydroxide, such as sodium hydroxide, potassium hydroxide, hydrated limeoxide, etc. is used.

The compounds of the general formula (I) can be separated from thehalide salt by-product e.g. by filtration or centrifugation. Thereafterthe solvent is removed from the solution containing the end-productpreferably by evaporation to dryness under reduced pressure. If desired,the thus-obtained free base can be purified, e.g., by recrystallizationfrom a suitable solvent, such as, an alcohol, acetone, ether, etc.

Any of the free bases of the general formula (I) can be converted intoits acid addition salt by reacting it with an appropriate organic ormineral acid.

The salt formation can be carried out directly in the reaction mixturewhere the bases of the general formula (I) were formed. In thisinstance, the end-products are separated in the form of their saltsformed with mineral or organic acids.

The optionally formed isomeric mixtures or acid addition salts thereofcan be separated by known methods to yield the individual isomers inpure state. The separation methods are based on the differences in thephysical or chemical properties of the respective isomers.

The compounds of the invention can be converted into pharmaceuticalproducts using organic or mineral carriers which are inert towards theactive agents and suitable for enteral or parenteral administration.

The pharmaceutical compositions may contain the new compounds of thegeneral formula (I) either alone or in combination with other knownactive agents.

If desired, the pharmaceutical products can be sterilized or admixedwith other auxiliary substances, such as, salts influencing the osmoticpressure, buffers, etc.

The invention is elucidated in detail by the aid of the followingnon-limiting Examples.

EXAMPLE 1 3,4-Dihydro-2H-(1,3)-thiazino[3,2-a]benzimidazole

15.0 g. (0.1 moles) of 2-mercapto-benzimidazole are suspended in 100 ml.of alcohol, and a solution of 8 g. (0.2 moles) of sodium hydroxide in 10ml. of water is added. Thereafter 15.7 g (0.1 moles) of1,3-chloro-bromo-propane are added to the obtained solution, and themixture is refluxed for about 3 hours. At the end of the reaction themineral salts cease to separate.

The separated mineral salts are removed by filtration and washed with aminimum amount of alcohol. The combined filtrate and wash is evaporatedto dryness under reduced pressure to yield 12.0 g. (63 %) of3,4-dihydro-2H-(1,3)-thiazino[3,2-a]benzimidazole; m.p.: 146°-147°C(heating rate: 4°C/min.) After recrystallization from alcohol, theproduct melts at 147°-148°C.

Analysis: Calculated for C₁₀ H₁₀ N₂ S (190.26): C: 63.13 %, H: 5.30 %,N: 14.72 %, S: 16,85 %, Found: C: 63.15 % H: 5.36 % N: 14.70 % S: 16.20%.

EXAMPLE 2 3,4-Dihydro-2H-(1,3)-thiazino[3,2-a]benzimidazolehydrochloride

The base obtained as described in Example 1 is dissolved in a mixture ofalcohol and acetone, and the solution is acidified to pH 3 withhydrochloric acid. The separated crystals are filtered off, washed anddried. This way 15,7 g. (90 %) of3,4-dihydro-2H-(1,3)-thiazino[3,2-a]benzimidazole hydrochloride areobtained; m.p.: 198°-199°C.

Analysis: Calculated for C₁₀ H₁₀ N₂ S.HCl (226.73): C: 52.98%, H: 4.89%,N: 12.36%, S: 14.14%, Cl:15.63%; Found: C: 53.05%, H: 5.20%, N: 12.13%,S: 14.00%, Cl:15.93%.

NMR-spectrum (in D₂ O):

7.25 (2h, m, =N--CH₂ --CH₂ --CH₂ --S--)

6.30 (2h, t, =N--CH₂ --CH₂ --CH₂ --S--)

5.52 (2h, t, =N--CH₂ --CH₂ --CH₂ --S--)

2.34 (4h, s, aromatic protons)

EXAMPLE 3 4,5-Dihydro-1H,3H-(1,4)-thiazepino[4,3-a]benzimidazole

16.4 G. (0.1 moles) of 2-mercapto-methylene-benzimidazole are dissolvedin 100 ml of methanol, and 11.2 g. (0.2 moles) of potassium hydroxidedissolved in a small amount of methanol are added, followed by 15.7 g.(0.1 moles) of 1,3-chloro-bromo-propane. The reaction mixture isrefluxed for 3 hours. At the end of the reaction, the mineral saltscease to separate.

The product is separated as described in Example 1. 15.1 G. (74 %) of4,5-dihydro-1H,3H-(1,4)-thiazepino[4,3-a]benzimidazole are obtained;m.p.: 155°-157°C (heating rate: 4°C/min.)

Analysis: Calculated for C₁₁ H₁₂ N₂ S (204.29): C: 64.67%, H: 5,92%, N:13.17% S: 15.70%; Found: C: 64.55%, H: 5.55%, N: 13.15%, S: 15.44%.

EXAMPLE 4 4,5-Dihydro-1H,3H-(1,4)-thiazepino[4,3-a]benzimidazolehydrochloride

One proceeds as described in Example 2 with the difference that the baseobtained in Example 3 is used as a starting substance. The product meltsat 172°-174°C (heating rate: 4°C/min.)

Analysis: Calcualted for C₁₁ H₁₂ N₂ S.HCl (240.75): C: 53.88%, H:5.44%,N: 11.63%, S: 13.32%, Cl: 14.73%; Found: C: 54.66%, H: 5.50%, N:11.90%,S: 13.25%, Cl: 14.44%.

EXAMPLE 53,4-Dihydro-3-hydroxy-7,8-dimethyl-2H-(1,3)-thiazino-[3,2-a]benzimidazole

17.8 G. (0.1 moles) of 2-thiol-5,6-dimethyl-benzimidazole are suspendedin 150 ml of ethanol, and a solution of 4.0 g. (0.1 moles) of sodiumhydroxide formed with 10 to 15 ml. of water is added. 9.2 G. (0.1 moles)of epichlorohydrine are added to the obtained solution, and the reactionmixture is refluxed for 3 hours.

The reaction mixture is processed as described in Example 1 to yield20.3 g. (87 %) of3,4-dihydro-3-hydroxy-7,8-dimethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole;m.p.: 266°-267°C (heating rate: 4°C/min.).

Analysis: Calculated for C₁₂ H₁₄ N₂ OS (234.32): C: 61.51%, H: 6.02%, N:11.96%, S: 13.69%; Found: C: 61.56% H: 6.13% N: 12.00% S: 13.36%.

NMR-spectrum (in trifluoroacetic acid):

7.48 (6H, s, --/CH₃ /₂)

6.20 (2h, m, =N--CH₂ --CH--CH₂ --S--)

5.30 to 5.50 (2H, m, =N--CH₂ --CH--CH₂ --S--)

4.65 to 4.85 (1H, m, =N--CH₂ --CH--CH₂ --S--)

2.50 (1h, s, aromatic proton)

2.58 (1H, s, aromatic proton)

EXAMPLE 63,4-Dihydro-3-hydroxy-7,8-dimethyl-2H-(1,3)-thiazino[3,2-a]benzimidazolehydrochloride

One proceeds as described in Example 2 with the difference that thecompound obtained according to Example 5 is used as starting substance.The product melts at 272°-274°C (heating rate: 4° C/min.).

Analysis: Calculated for C₁₂ H₁₄ N₂ OS.HCl (270.78): C: 53.23%, H:5.58%, N: 10.35%, S: 11.84%, Cl: 13.10%; Found: C: 53.24%, H: 6.01%, N:10.54%, S: 12.07%, Cl: 13.14%.

In the following Examples, the bases are prepared as described inExamples 1, 3 or 5, while the acid addition salts are prepared asdescribed in Example 2.

EXAMPLE 7 2,3-Dihydro-(1,3)-thiazolo[3,2-a]benzimidazole

The compound melts at 239°-240°C (heating rate: 4°C/min.).

Analysis: Calculated for C₉ H₈ N₂ S (178.12): C: 61.34%, H: 4.57%, N:15.90%, S: 18.19%; Found: C: 60.59%, H: 4.60%, N: 15.69%, S: 18.62%.

EXAMPLE 8 2,3-Dihydro-(1,3)-thiazolo[3,2-a]benzimidazole hydrochloride

The compound melts at 217°-219°C (heating rate: 4°C/min.).

Analysis: Calculated for C₉ H₈ N₂ S.HCl (212.70): C: 50.82%, H: 4.26%,N: 13.17%, S: 15.08%, Cl: 16.67%; Found: C: 50.75%, H: 4.39%, N: 13.17%,S: 14.83%, Cl: 16.84%.

NMR-spectrum (in D₂ O): 6.07 (4H, s, --CH₂ --CH₂ --), 2.40 (4H, s,aromatic protons)

EXAMPLE 9 4,5-Dihydro-2H,3H-(1,3)-thiazepino[3,2-a]benzimidazolehydrochloride

The compound melts at 128°-129°C (heating rate: 4°C/min.).

Analysis: Calculated for C₁₁ H₁₂ N₂ S.HCl (240.75): C: 54.88%, H: 5.44%,N: 11.64%, S: 13.32%, Cl: 14.72%, Found: C: 54.30%, H: 5.24%, N: 11.72%,S: 13.28%, Cl: 15.10%.

EXAMPLE 10 3,4-Dihydro-3-hydroxy-2H-(1,3)-thiazino[3,2-a]benzimidazole

The compound melts at 214°-215°C (heating rate: 4°C/min.).

Analysis: Calculated for C₁₀ H₁₀ N₂ S (206.26): C: 58.23%, H: 4.89%, N:13.58%, S: 15.54%; Found: C: 58.33%, H: 5.21%, N: 13.42%, S: 15.22%.

NMR-spectrum (in trifluoroacetic acid):

6.20 (2H, m, =N--CH₂ --CH--CH₂ --S--)

5.36 (2h, m, =N--CH₂ --CH--CH₂ --S--)

4.75 (1h, m, =N--CH₂ --CH--CH₂ --S--)

2.83 (4h, s, aromatic protons)

EXAMPLE 11 3,4-Dihydro-3-hydroxy-2H-(1,3)-thiazino[3,2-a]benzimidazolehydrochloride

The compound melts at 211°-212°C (heating rate: 4°C/min).

Analysis: Calculated for C₁₀ H₁₀ N₂ S.HCl (242.73): C: 49.48%, H: 4.57%,N: 11.54%, S: 13.21%, Cl: 14.61%; Found: C: 49.44%, H: 4.93%, N: 11.44%,S: 13.37%, Cl: 14.45%.

NMR-spectrum (in D₂ O):

6.22 (2h, t, =N--CH₂ --CH--CH₂ --S--)

5.46 (2h, t, =N--CH₂ --CH--CH₂ --S--)

4.95 (1h, m, =N--CH₂ CH--CH₂ --S--)

2.33 (4h, s, aromatic protons)

EXAMPLE 124,5-Dihydro-4-hydroxy-1H,3H-(1,4)-thiazepino[4,3-a]benzimidazole

The compound melts at 231°-233°C (heating rate: 4°C/min.)

Analysis: Calculated for C₁₁ H₁₂ N₂ OS (220.29): C: 59.97%, H: 5.49%, N:12.72%, S: 14.56%; Found: C: 60.44%, H: 5.47%, N: 12.76%, S: 14.20%.

NMR-spectrum (in trifluoroacetic acid):

6.48 (2H, m, =N--CH₂ --CH--CH₂ --S--)

5.58 (2h, s, --CH₂ --S--)

4.80 to 5.38 (3H, m, = N--CH₂ --CH--CH₂ --S--)

2.20 (4h, s, aromatic protons)

EXAMPLE 134,5-Dihydro-4-hydroxy-1H,3H-(1,4)-thiazepino[4,3-a]benzimidazolehydrochloride

The compound melts at 191°-192°C (heating rate: 4°C/min.)

Analysis: Calculated for C₁₁ H₁₂ N₂ OS.HCL (256.75) C: 51.46%, H: 5.10%,N:10.91%, S:12.49%, Cl:13.81%; Found: C: 50.96%, H: 5.46%, N:10.85%,S:12.53%, Cl:13.36%.

EXAMPLE 143,4-Dihydro-7,8-dimethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole

The compound melts at 225°-226°C (heating rate: 4°C/min.)

Analysis: Calculated for C₁₂ H₁₄ N₂ S (218.32): C: 66.02%, H: 6.46%, N:12.83%, S: 14.69%; Found: C: 65.93% H: 6.54% N: 12.50% S: 15.01%.

EXAMPLE 153,4-Dihydro-7,8-dimethyl-2H-(1,3)-thiazino[3,2-a]benzimidazolehydrochloride

The compound melts at 218°-220°C (Heating rate 4°C/min.)

Analysis: Calculated for C₁₂ H₁₄ N₂ S.HCl (254.78): C: 56.57%, H: 5.39%,N: 11.00%, S: 12.59%, Cl: 13.91%; Found: C: 56.92%, H: 5.10%, N: 10.85%,S : 12.73%, Cl: 13.61%.

NMR-spectrum (in D₂ O):

8.72 (6h, s, /CH₃ /₂)

7.40 to 8.70 (2H, m, = N--CH₂ --CH₂ --S--)

6.50 (2h, t, =N--CH₂ --CH₂ --CH₂ --S--)

5.85 (2h, m, =N--CH₂ --CH₂ --CH₂ --S--)

2.85 (1h, s, aromatic proton)

2.75 (1H, s, aromatic proton)

EXAMPLE 163,4-Dihydro-8,9-dimethyl-2H,2H-(1,3)-thiazepino[3,2-a]benzimidazolehydrochloride

The compound melts at 138°-139°C (heating rate: 4°C/min.).

Analysis: Calculated for C₁₃ H₁₆ N₂ S.HCl (2.68.81): C: 58.09%, H:6.37%, N: 10.42%, S: 11.93%, Cl: 13.19%; Found: C: 58.26%, H: 6.45%, N:10.67%, S: 11.87%, Cl: 13.03%.

EXAMPLE 17 3,4-Dihydro-7-chloro-2H-(1,3)-thiazino[3,2-a]benzimidazole

The compound melts at 178°-179°C (heating rate: 4°C/min.),

Analysis: Calculated for C₁₀ H₉ ClN₂ OS (240.71): C: 49.90%, H: 3.77%,N: 11.64%, S: 13.32%, Cl: 14.73%; Found: C: 50.22%, H: 3.11%, N: 11.97%,S: 13.67%, Cl: 14.28%.

EXAMPLE 18 3,4-Dihydro-2H-(1,3)-thiazino[3,2-a]pyrido[3,2-d]imidazoledihydrochloride

The compound melts at 182°-183°C (heating rate: 4°C/min.).

Analysis: Calculated for C₉ H₉ N₃ S.2HCl (267.17): C: 40.93%, H: 4.19%,N: 15.91%, S: 12.12%, Cl: 26.84%; Found: C: 40.40%, H: 4.40%, N: 16.03%,S: 12.32%, Cl: 26.48%.

NMR-spectrum (in D₂ O):

7.45 (2h, m, =N--CH₂ --CH₂ --S--)

6.46 (2h, m, =N--CH₂ --CH₂ --CH₂ --S--)

5.50 (2h, m, =N--CH₂ --CH₂ --CH₂ --S--)

1.50 to 2.50 (3H, pyridine protons)

EXAMPLE 193,4-Dihydro-3-hydroxy-2H-(1,3)-thiazino[3,2-a]pyrido[3,2-d]imidazolehydrochloride

The compound melts at 183°-185°C (heating rate: 4°C/min.).

Analysis: Calculated for C₉ H₉ N₃ OS.HCl (243.71): C: 44.36%, H: 4.13%,N: 17.25%, S:13.16%, Cl: 14.54%; Found: C: 44.25%, H: 4.10%, N: 17.63%,S:13.27%, Cl: 14.52%. EXAMPLE 203,4-Dihydro-2H-(1,3)-thiazino[3,2-a]pyrimidino[5,4-d]imidazole

The compound melts at 128°-130°C (heating rate: 4°C/min.).

Analysis: Calculated for C₈ H₈ N₄ S (192.24): C: 49.99%, H: 4.19%, N:29.14%, S: 16.68%; Found: C: 50.06%, H: 4.37%, N: 29.21%, S: 16.45%.

EXAMPLE 21 3,4-Dihydro-2H-(1,3)-thiazino [3,2-a]pyrimidino[5,4-d]imidazole hydrochloride

The compound melts at 180°-182°C (heating rate: 4°C/min.).

Analysis: Calculated for C₈ H₈ N₄ S.HCl (228.70): C: 42.02%, H: 3.96%,N: 24.50%, S: 14.02%, Cl: 15.50%; Found: C: 42.01%, H: 4.07%, N: 23.90%,S: 14.14%, Cl: 15.50%.

NMR-spectrum (in D₂ O):

7.32 (2h, m, =N--CH₂ --CH₂ --CH₂ --S--)

6.45 (2h, t, =N--CH₂ --CH₂ --CH₂ --S--)

5.38 (2h, t, =N--CH₂ --CH₂ --CH₂ --S--)

0.58 to 0.80 (2H, m, pyrimidine protons)

EXAMPLE 223,4-Dihydro-6-hydroxy-8-amino-2H-(1,3)-thiazino[3,2-a]pyrimidino[5,4-d]imidazole

The compound melts at 300°C (heating rate: 4°C/min.).

Analysis: Calculated for C₈ H₉ N₅ OS (225.25): C: 43.05%, H: 4.06%, N:31.37%, S: 14.36%; Found: C: 43.09%, H: 4.17%, N: 30.97%, S: 13.71%.EXAMPLE 233,4-Dihydro-6-hydroxy-8-amino-2H-(1,3)-thiazino[3,2-a]pyrimidino[5,4-d]imidazolehydrochloride

The compound melts at 350°C (heating rate; 4°C/min.).

Analysis: Calculated for C₈ H₉ N₅ OS.HCl (259.71): C:37.00%, H: 3.88%,N: 26.97%, S: 12.34%, Cl: 13.65%; Found: C: 36.86%, H: 3.49%, N: 26.89%,S: 12.50%, Cl: 13.34%.

EXAMPLE 24 3,4-Dihydro-3,6-dihydroxy-8-amino-(1,3)-thiazino[3,2-a]pyrimidino[5,4-d]imidazole dihydrochloride

The compound melts at 340°C (heating rate: 4°C/min.).

Analysis: Calculated for C₈ H₉ N₅ O₂ S.2HCl (312.17): C: 30.78%, H:3.55%, N: 22.43%, S: 10.27%, Cl: 22.72%; Found: C: 30.45%, H: 3.49%, N:22.60%, S: 9.93%, Cl: 22.23%.

EXAMPLE 25 2,3-Dihydro-7-chloro-(1,3)-thiazolo[3,2-a]benzimidazolehydrochloride

The compound melts at 176°-178°C (heating rate: 4°C/min.)

Analysis: Calculated for C₉ H₇ ClN₂ S.HCl (247.15): C: 43.74%, H: 3.27%,N: 11.33%, S: 12.97%, Cl: 28.69%; Found: C: 43.60%, H: 3.55%, N: 11.20%,S: 12.69%, Cl: 28.82%.

EXAMPLE 262,3-Dihydro-7-nitro-(1,3)-thiazolo[3,2-a]benzimidazolehydrochloride

The compound melts at 180°-182°C (heating rate: 4°C/min.).

What we claim is:
 1. A tricyclic fused imidazole derivative of theformula (I), ##SPC5##wherein R₁ stands for hydrogen or hydroxy, n isequal to zero or one, m is equal to zero or one, m+n=1, A stands for agroup of the formula (II), ##EQU7## wherein R₂ represents hydrogen orhydroxy,R₃ represents hydrogen or amino, and Q and Z each stand fornitrogen or a =CH-- group, or A stands for a group of the formula (III),##EQU8## wherein R₄ and R₅ each represent hydrogen, methyl, chlorine ornitro, or an acid additional salt thereof. 2.3,4-Dihydro-3-hydroxy-2H-(1,3)-thiazino[3,2-a]benzimidazole or an acidaddition salt thereof. 3.3,4-Dihydro-3-hydroxy-7,8-dimethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole or an acid addition salt thereof. 4.3,4-Dihydro-2H-(1,3)-thiazino[3,2-a]pyrido[3,2-d]imidazole or an acidaddition salt thereof.